1. Field of the Invention
Prophylaxis and treatment of obesity, coronary artery disease, infertility, diabetes, and related diseases and conditions can be effected through novel C-reactive protein antagonist polypeptides and nucleic acid molecules encoding the same. Also provided are pharmaceutical compositions and methods for the treatment, amelioration, and/or prevention of diseases and/or conditions associated with C-reactive protein.
2. Background
Molecular and physiological evidence accumulated in the past decade has firmly established leptin as a critical adipocyte hormone involved in regulation of energy-intake and expenditure, weight, fertility, as well as glucose and lipid metabolism. J. M. Friedman et al., 1998, Nature 395, 763; R. S. Ahima et al., 2000, Ann. Rev. Physiol. 62, 413.
Null mutations in leptin or leptin receptor genes cause hyperphagia, severe obesity, sterility, and diabetes in both rodents and humans. R. S. Ahima et al., 2000, Ann. Rev. Physiol. 62, 413; Y. Zhang et al., 1994, Nature 372, 425; G. H. Lee et al., 1996, Nature 379, 632. Leptin replacement in these animals as well as in humans with leptin deficiency can have profound effects to reverse obesity. However, the great majority of overweight and obese individuals have elevated rather than depressed levels of leptin. A. H. Luke et al., 1998, Am. J. Clin. Nutr. 67, 391; P. J. Havel, 1998, Am. J. Clin. Nutr. 67, 355; and M. W. Schwartz et al., 1997, Diabetes Care 20, 1476.
It remains to be established why high leptin concentration in obesity fails to suppress food intake and reduce adiposity. Therapeutic trials with exogenous leptin that further raised leptin levels have failed to induce meaningful weight loss. S. B. Heymsfield et al., 1999, JA.M.A. 282, 1568. These observations have spawned the concept of “leptin resistance.” T. Gura, 1999, Science 286, 881 ( ); C. Bjorbaek et al., J. Biol. Chem. 274, 30059 (Oct. 15, 1999).
Recent studies attempted to elucidate potential molecular mechanisms. Elevation of a suppressor of cytokine signaling-3 (SOCS-3), perhaps induced by leptin itself, might diminish leptin actions in the central nervous system and pancreatic β-cells. C. Bjorbaek et al., 1999, J. Biol. Chem. 274, 30059; Z. Wang et al., 2000, Biochem. Biophys. Res. Commun. 277, 20. Those observations do not fully explain leptin resistance. For example, this mechanism does not account for impaired leptin transport into the central nervous system (CNS), which has been consistently observed in obesity. M. W. Schwartz et al., Nat. Med. 2, 589 (1996).
C-reactive protein (CRP) is commonly elevated in obesity and is a marker of the low-grade inflammatory state associated with obesity and increased cardiovascular risk of obesity. M. Maachi et al., 2004, Int. J. Obes. Relat. Metab. Disord. 28, 993; J. T. Willerson et al., 2004, Circulation 109, 112; M. B. Schulze et al., 2004, Diabetes Care 27, 889. Elevation of CRP and its relationship to obesity and other disorders has not been adequately explained.
The mechanism by which high leptin concentration fails to influence regulation of energy-intake and expenditure, weight, fertility, and glucose and lipid metabolism in a majority of obese humans remains a mystery. Although some have speculated that there is a form of leptin resistance, no studies have been published showing how this might occur, nor have any studies identified the factors that might influence it. Likewise, there is no accepted explanation why CRP is elevated in obesity and other conditions. As such, CRP may be nothing more than a mere marker for such conditions.